title: Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy.
abstract: Histone deacetylases (HDACs) regulate cardiac plasticity; however, their molecular targets are unknown. As autophagy contributes to pathological cardiac remodeling, we hypothesized that HDAC inhibitors target autophagy. The prototypical HDAC inhibitor (HDACi), trichostatin A (TSA), attenuated both load- and agonist-induced hypertrophic growth and abolished the associated activation of autophagy. Phenylephrine (PE)-triggered hypertrophy and autophagy in cultured cardiomyocytes were each blocked by a panel of structurally distinct HDAC inhibitors. RNAi-mediated knockdown of either Atg5 or Beclin 1, two essential autophagy effectors, was similarly capable of suppressing ligand-induced autophagy and myocyte growth. RNAi experiments uncovered the class I isoforms HDAC1 and HDAC2 as required for the autophagic response. To test the functional requirement of autophagic activation, we studied mice that overexpress Beclin 1 in cardiomyocytes. In these animals with a fourfold amplified autophagic response to TAC, TSA abolished TAC-induced increases in autophagy and blunted load-induced hypertrophy. Finally, we subjected animals with preexisting hypertrophy to HDACi, finding that ventricular mass reverted to near-normal levels and ventricular function normalized completely. Together, these data implicate autophagy as an obligatory element in pathological cardiac remodeling and point to HDAC1/2 as required effectors. Also, these data reveal autophagy as a previously unknown target of HDAC inhibitor therapy.
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dian J
authors.initials: DJ
authors.lastname: Cao
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Cyndi R
authors.initials: CR
authors.lastname: Morales
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D056572:Histone Deacetylase Inhibitors; D010656:Phenylephrine